De novo protein design by citizen scientists

Brian Koepnick, Jeff Flatten, Tamir Husain, Alex Ford, Daniel-Adriano Silva, Matthew J. Bick, Aaron Bauer, Gaohua Liu, Yojiro Ishida, Alexander Boykov, Roger D. Estep, Susan Kleinfelter, Toke Nørgård-Solano, Linda Wei, Foldit Players, Gaetano T. Montelione, Frank DiMaio, Zoran Popović, Firas Khatib, Seth Cooper and David Baker ()
Additional contact information
Brian Koepnick: University of Washington
Jeff Flatten: University of Washington
Tamir Husain: University of Washington
Alex Ford: University of Washington
Daniel-Adriano Silva: University of Washington
Matthew J. Bick: University of Washington
Aaron Bauer: University of Washington
Gaohua Liu: Rutgers University The State University of New Jersey
Yojiro Ishida: Rutgers The State University of New Jersey
Gaetano T. Montelione: Rutgers University The State University of New Jersey
Frank DiMaio: University of Washington
Zoran Popović: University of Washington
Firas Khatib: University of Massachusetts Dartmouth
Seth Cooper: Northeastern University
David Baker: University of Washington

Nature, 2019, vol. 570, issue 7761, 390-394

Abstract: Abstract Online citizen science projects such as GalaxyZoo1, Eyewire2 and Phylo3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson–Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now—starting from an extended polypeptide chain—generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds—including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.

Date: 2019
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DOI: 10.1038/s41586-019-1274-4

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